Obesity is a major public health problem that impacts nearly a third of the US population. Evidence from epidemiological studies indicates that obesity is associated with the development of many types of cancer and its connection with liver cancer is particularly strong. In the US, obesity is associated with a high incidence of non-alcoholic-induced fatty liver disease (NAFLD) and liver cancer. The mechanisms underlying the increased risk of liver cancer in obese population are not fully understood. Because fatty tissues release hormones that promote inflammation, it is believed that chronic inflammation in fatty liver disease commonly seen in obese people is the culprit. In this two-PI project, we will focus on lipid peroxidation (LPO)-induced DNA damage and its effects on DNA repair and mutagenesis, and their roles in hepatocellular carcinoma (HCC) development. We propose that the formation of endogenous cyclic DNA adducts, including the propano Acr-dG and HNE-dG, the etheno of dA and dG, and the recently discovered DHH-etheno dA and DHH-etheno dG, from aldehydes generated by fatty acid oxidation as a result of chronic inflammation is increased in NAFLD; concomitantly, these aldehydes can also inhibit DNA repair mechanisms. We believe that these effects can induce mutations at driver genes for the promotion of hepatocarcinogenesis through non-alcoholic-induced steatohepatitis (NASH), a progressive form of NAFLD. We propose to use the genetically predisposed obese C57BL/6 (B-6) mice as a model, which are prone to develop NAFLD and HCC, in parallel with cultured mouse and human hepatocytes, to examine the hypothesis by carrying out the following aims: 1) to determine the formation of cyclic DNA adducts in livers of B-6 mice fed high fat diet during the course of HCC development; 2) to determine the mutational spectrum and map the distribution of bulky cyclic DNA adducts and oxidative-DNA damage (ODD) in two liver cancer driver genes, p53 and ?-catenin (CTNNB1), in livers of B-6 mice during the NAFLD and HCC stages and in cultured hepatocytes treated with LPO aldehyde byproducts; 3) to determine the effects of LPO aldehydes on DNA repair capacity and mutational susceptibility; and 4) to examine the potential chemopreventive activities of lipoic acid and Polyphenon E for HCC development in obese B-6 mice.